The Clinical Genetics Branch (CGB) integrates molecular and clinical observations in cancer genetics into an interdisciplinary approach involving epidemiologic, clinical, genetic, behavioral, statistical and laboratory methods to define the role of susceptibility genes in cancer etiology. The primary goal of this research program is translate recent dramatic advances in molecular genetics into evidence-based management strategies for persons at increased genetic risk of cancer. The central research strategy relies upon the detailed and meticulous assessment of the individual members of cancer-prone families. The first major clinical research project undertaken by CGB represents the next stage in DCEG's long-standing commitment to the study of hereditary breast and ovarian cancer (HBOC). Responsibility for the ongoing follow-up, and for the next generation of analytic studies, of the Genetic Epidemiology Branch's cohort of 26 HBOC families with mutations in either BRCA1 or BRCA2 (including 216 individuals tested or inferred to be positive for BRCA1/2 mutations and 392 family members tested as mutation negative) has been transferred to CGB. The first priority with regard to these families is to make clinical predictive genetic testing for BRCA1/2 mutations available to interested family members. Concurrently, we will mount a carefully-designed research protocol for these same individuals. This project will address issues related to breast cancer screening, early diagnosis, behavioral, educational and psychosocial dynamics related to the process of genetic risk assessment and testing, endogenous hormones as contributors to the risk of hereditary breast cancer, and decision-making by family members related to the use of tamoxifen as a breast cancer chemoprevention strategy. The Concept and Protocol related to this study are now under development. The first component of this study to begin patient accrual is a pilot study assessing mammography, MRI and PET imaging as screening tools for women at increased genetic risk of breast cancer. This protocol has cleared both the DCEG scientific review process and and has been approved by the Clinical Center IRB and is expected to enroll its first subjects within the next several months. This project will also assess the impact of menstrual cycle timing on breast MRI imaging characteristics, and provide us with an opportunity to evaluate breast duct lavage, a new technique for obtaining breast duct epithelial cells, as an early diagnosis tool in this setting, and as a potential source of biological materials for molecular genetic studies. A study of the prevalence of BRCA1/2 founder mutations is now underway in a series of 1000 Ashkenazi Israelis with prostate cancer during 1994 - 1995. The genetic testing on these samples is expected to be completed before the end of the year. In collaboration with the Laboratory of Pathology/DCS, a systematic comparison of the histopathology of BRCA1/2 mutation associated prostate cancers with that of cancers not associated with such mutations is planned. We also will perform loss of heterozygosity studies on BRCA1,2-associated prostate cancers. The goal of this study is to resolve the current uncertainty regarding whether prostate cancer is one of the features of the BRCA1,2 syndromes. If the answer proves to be "yes," this will provide the rationale for proceeding with a study of prostate cancer screening and prevention among the men from our HBOC families who are mutation carriers. Among the many pressing clinical issues in the management of women who carry mutations in BRCA1/2 is the appropriate role of prophylactic oophorectomy as a risk reduction strategy. In collaboration with investigators from the Gynecologic Oncology Group (GOG) and the Ovarian Cancer Early Detection Resource Network (EDRN), plans are well underway to mount a national, prospective follow-up study of genetically at-risk women who elect to undergo prophylactic oophorectomy. This will permit us to address such issues as: (a) what is the prevalence of clinically occult ovarian cancer at the time of prophylactic oophorectomy? (b) are there identifiable precursor lesions in the ovaries of genetically at-risk women? (c) what is the incidence of primary peritoneal carcinomatosis and breast cancer subsequent to this operation? and (d) how does this surgical procedure affect the quality of life for the women who elect it? Another major issue related to BRCA1,2-associated ovarian cancer is the lack of effective screening measures for this often lethal disease. A Workshop has been scheduled for April 2001 to address this deficiency and to attempt to identify novel screening strategies which warrant further clinical evaluation. We are also negotiating a collaboration with an extra-mural investigator who has collected a large, population-based series of ovarian cancer cases and controls. The intent would be to determine the BRCA1/2 mutation status of the subjects in this study, providing both a more accurate estimate of the proportion of ovarian cancers which can be attributed to this genetic alteration, and permitting a detailed analysis of how mutation status and exposure to oral contraceptives interact with regard to ovarian cancer risk. It is vital to determine whether women at hereditary risk of ovarian cancer experience the same protective benefit from the use of oral contraceptives as that which has been documented among women in the general population. We have initiated development of a multidisciplinary research program which will focus on the inherited pediatric disorders which predispose to bone marrow failure, acute leukemia and, in adult survivors, solid tumors as well. Fanconi's Anemia is the prototype of these diseases, which also include dyskeratosis congenita, Diamond-Blackfan syndrome and Schwachman-Diamond syndrome. These rare disorders will be used as models for studying mechanisms of carcinogenesis in humans. This opportunity has been created by the recruitment of a prominent clinical investigator (Dr. Blanche P. Alter), who has an international reputation in both the clinical management and the laboratory assessment of patients with these disorders. As the staff of CGB increases in number, it is expected that additional, less well studied familial/inherited cancer susceptibility disorders will be selected for study. The first of these is familial testicular cancer, an entity in which DCEG has had an intermittent interest in over the years. The recent mapping of a testicular cancer susceptibility gene to the X chromosome, coupled with the impending activation of a new, large testicular cancer case-control study by epidemiology colleagues in the Environmental Epidemiology Branch have resulted in CGB committing to a major familial testicular cancer project. We have joined the International Testicular Cancer Linkage Consortium, and contributed to their gene mapping/cloning efforts DNA from a series of families previously studied at NCI some years ago. We are negotiating to take the lead in a central review of the testicular cancer pathology and an analysis of the occurrence of cancers other than germ cell tumors in the Consortium family set. A mechanism for accruing new testicular cancer families has been developed, and we expect to acquire DNA for positional cloning purposes from them, as well as to invite selected families to the NIH Clinical Center for a more detailed, etiologically oriented, clinical/genetic/laboratory study of the type that has historically been done so well by DCEG investigators. The combination of breast cancer and colon cancer in different members of the same family seems to occur more often than can be accounted for by the known hereditary cancer syndromes. We are planning a family/genetic study of women with double primary cancers of the breast and colon in an effort to clarify this association. Evidence for an as yet unidentified cancer susceptibility gene will be sought. High on the list of other likely studies is the systematic investigation of familial hematopoietic and lymphoproliferative disorders, with special attention to families with multiple different cancers of this type. This would build on prior DCEG studies of familial Hodgkins and acute leukemia, and current studies of familial non-Hodgkins lymphoma, chronic lymphocytic leukemia and Waldenstrom's macroglobulinemia. CGB will also play a role, as needed, in the analysis of family history data collected as part of ongoing analytic epidemiology studies conducted by colleagues elsewhere within DCEG. The first such project entails an assessment of family history of cancer and level of Westernization as cancer risk factors in a population-based, case-control study of breast cancer in Asian American women. This is being done through a collaboration with investigators in the Epidemiology and Biostatistics Program, and the Genetic Epidemiology Branch.